Azetidine Derivatives

ABSTRACT

Ar1 is optionally substituted phenyl or optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms; Ar2 is optionally substituted phenyl, optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms or optionally substituted fused bicyclic heteroaryl having 5 or 6 ring atoms in each fused ring; and Ar3 is a divalent radical selected from optionally substituted phenylene and optionally substituted monocyclic heteroarylene radicals having 5 or 6 ring atoms.

This invention relates to a class of azetidine derivatives which areinhibitors of fatty acid amide hydrolase, (FAAH), and which are usefulin the treatment of diseases or medical conditions which benefit frominhibition of FAAH activity, such as anxiety, depression pain,inflammation, and eating, sleep, neurodegenerative and movementdisorders.

BACKGROUND TO THE INVENTION

The endogenous agonists of the cannabinoid receptors CB1 and CB2 Includethe fatty acid amide anandamide (AEA). AEA is hydrolysed to arachidonicacid by the membrane bound protein fatty add amide hydrolase (FAAH).FAAH was characterized in 1996 by Cravatt and co-workers (Cravatt,Nature 1996, 384, 83). It was subsequently determined that FAAH isadditionally responsible for the catabolism of a large number ofimportant lipid signaling fatty acid amides including: another majorendocannabinoid, 2-arachidonoylglycerol (2-AG) (Science 1992, 258,1946-1949); the sleep-inducing substance, oleamide (Science 1995, 268,1506); the appetite-suppressing agent, N-oleoylethanolamine (OEA)(Rodriguez de Fonesca, Nature 2001, 414, 209); and the anti-inflammatoryagent, palmitoylethanolamide (PEA) (Lambert, Curr. Med. Chem. 2002,9(6), 663).

Inhibitors of FAAH are being sought since such inhibitors elevate theconcentrations of these endogenous signaling lipids and thereby produceassociated beneficial pharmacological effects. There have been somereports of the effects of various FAAH inhibitors in pre-clinicalmodels. Those effects include analgesic properties (see WO 02/087569, WO04/033652); anxiety (Kathuria, Nat. Med. 2003, 9(1), 76); spasticity(Baker, FASEB J. 2001, 15(2), 300).

Results of research on the effects of certain exogenous cannabinoidsalso suggest that a FAAH inhibitor may be useful for treating variousconditions, diseases, disorders, or symptoms. These include pain,nausea/emess, anorexia, spasticity, movement disorders, epilepsy andglaucoma. To date, approved therapeutic uses for cannabinoids includethe relief of chemotherapy-induced nausea and emesis among patients withcancer and appetite enhancement in patients with HIV/AIDS who experienceanorexia as a result of wasting syndrome.

Apart from the approved indications, a therapeutic field that hasreceived much attention for cannabinoid use is analgesia, i.e., thetreatment of pain. Five small randomized controlled trials showed thattetrahydrocannabinol THC is superior to placebo, producing dose-relatedanalgesia (Robson, Br. J. Psychiatry 2001, 178, 107-115).

A number of individuals with multiple sclerosis have claimed a benefitfrom cannabis for both disease-related pain and spasticity, with supportfrom small controlled trials (Svendsen, Br. Med. J. 2004, 329, 253).Likewise, various victims of spinal cord injuries, such as paraplegia,have reported that their painful spasms are alleviated after smokingmarijuana. A report showing that cannabinoids appear to controlspasticity and tremor in the CREAE model of multiple sclerosisdemonstrated that these effects are mediated by.

CB1 and CB2 receptors (Baker, Nature 2000, 404, 84-87). Phase 3 clinicaltrials have been undertaken in multiple sclerosis and spinal cord injurypatients with a narrow ratio mixture of tetrahydrocannabinol/cannabidiol(THC/CBD). Cannabinoids produced dose-related reductions in intraocularpressure (IOP) and therefore may relieve glaucoma symptoms.Ophthalmologists have prescribed cannabis for patients with glaucoma inwhom other drugs have failed to adequately control intraocular pressure(Robson, 2001 supra).

In addition to the effects of a FAAH inhibitor on AEA and otherendocannabinoids, inhibitors of FAAH's catabolism of other lipidmediators may be used in treating other therapeutic indications. Forexample, PEA has demonstrated biological effects in animal models ofinflammation, immunosuppression, analgesia, and neuroprotection (Ueda,J. Biol. Chem. 2001, 276(38), 35552). Oleamide, another substrate ofFAAH, induces sleep (Boger, Proc. Natl. Acad. Sci. USA 2000, 97(10),5044; Mendelson, Neuropsychopharmacology 2001, 25, S36).

FAAH inhibitors are considered potentially useful in treatingAlzheimer's Disease, schizophrenia, depression, alcoholism, addiction,suicide, Parkinson's disease, Huntington's disease, stroke, emesis,miscarriage, embryo implantation, endotoxic shock, liver cirrhosis,atherosclerosis, cancer, traumatic head injury, glaucoma, and bonecement implantation syndrome.

Other diseases or medical conditions that would potentially benefit frominhibition of FAAH activity, include, for example, multiple sclerosis,retinitis, amyotrophic lateral sclerosis, immunodeficiency virus-inducedencephalitis, attention-deficit hyperactivity disorder, pain,nociceptive pain, neuropathic pain, inflammatory pain, non-inflammatorypain, painful hemorrhagic cystitis, obesity, hyperlipidemia, metabolicdisorders, feeding and fasting, alteration of appetite, stress, memory,aging, hypertension, septic shock, cardiogenic shock, intestinalinflammation and motility, irritable bowel syndrome, colitis, diarrhea,ileitis, ischemia, cerebral Ischemia, hepatic ischemia, myocardialInfarction, cerebral excitotoxicity, seizures, febrile seizures,neurotoxicity, neuropathies, sleep, induction of sleep, prolongation ofsleep, insomnia, and inflammatory diseases.

Neurological and psychological diseases or conditions that wouldpotentially benefit from inhibition of FAAH activity include, forexample, pain, depression, anxiety, glaucoma, nausea, emesis, loss ofappetite, sleep disturbances, respiratory disorders, allergies,traumatic brain injury, stroke, generalized anxiety disorder (GAD),obsessive compulsive disorders, stress; stress urinary incontinence,attention deficit hyperactivity disorders, schizophrenia, psychosis,Parkinson's disease, muscle spasticity, epilepsy, dyskenesia, seizuredisorders, jet lag, and insomnia.

Other diseases or medical conditions that would potentially benefit frominhibition of FAAH activity, include, for example, a variety ofmetabolic syndromes, diseases, disorders and/or conditions, includingbut not limited to, insulin resistance syndrome, diabetes,hyperlipidemia, fatty liver disease, obesity, atherosclerosis andarteriosclerosis.

FAAH inhibitors are potentially useful in the treatment of a variety ofpainful syndromes, diseases, disorders and/or conditions, including butnot limited to those characterized by non-inflammatory pain,inflammatory pain, peripheral neuropathic pain, central pain,differentiation pain, chronic nociceptive pain, stimulus of nociceptivereceptors, phantom and transient acute pain.

Inhibition of FAAH activity can also potentially be used in thetreatment of a variety of conditions involving inflammation. Theseconditions include, but are not limited to arthritis (such as rheumatoidarthritis, shoulder tendonitis or bursitis, gouty arthritis, andpolymyalgia rheumatica), organ-specific inflammatory diseases (such asthyroiditis, hepatitis, inflammatory bowel diseases), asthma, otherautoimmune diseases (such as multiple sclerosis), chronic obstructivepulmonary disease (COPD), allergic rhinitis, and cardiovasculardiseases.

FAAH inhibitors are potentially useful in preventing neurodegenerationor for neuroprotection.

In addition, it has been shown that when FAAH activity is reduced orabsent, one of its substrates, anandamide, acts as a substrate forCOX-2, which converts anandamide to prostamides (Weber et al. J. Lipid.Res. 2004; 45:757). Concentrations of certain prostamides may beelevated in the presence of a FAAH inhibitor. Certain prostamides areassociated with reduced intraocular pressure and ocular hypotensivity.Thus, FAAH inhibitors may be useful for treating glaucoma.

BRIEF SUMMARY OF THE INVENTION

This invention makes available a class of azetidine derivatives, morefully defined and described below, having FAAH inhibitory activity. Thecompounds of the invention are useful for treatment of diseases ormedical conditions which benefits from inhibition of FAAH activity. Suchdiseases or conditions have been described above. In particular thecompounds of the invention may be used in the treatment of anxiety,depression, pain, inflammation, a sleep disorder or a movement disorder.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt thereof:

whereinAr¹ is optionally substituted phenyl or optionally substitutedmonocyclic heteroaryl having 5 or 6 ring atoms;Ar² is optionally substituted phenyl, optionally substituted monocyclicheteroaryl having 5 or 6 ring atoms or optionally substituted fusedbicyclic heteroaryl having 5 or 6 ring atoms in each fused ring; andAr³ is a divalent radical selected from the group consisting ofoptionally substituted phenylene and optionally substituted monocyclicheteroarylene radicals having 5 or 6 ring atoms.

In other aspects, the invention provides.

(a) a pharmaceutical composition comprising a compound of formula (I)above or a pharmaceutically acceptable salt thereof, together with oneor more pharmaceutically acceptable carriers and/or excipients;(b) The use of compound of formula (I) above or a pharmaceuticallyacceptable salt thereof, for treatment of a disease or medical conditionwhich benefits from inhibition of FAAH activity;(c) a method of treatment of a disease or medical condition whichbenefits from Inhibition of FAAH activity, comprising administering to asubject suffering such disease or condition an effective amount ofcompound of formula (I) above or a pharmaceutically acceptable saltthereof

Diseases or medical conditions which benefit from inhibition of FAAHactivity include those referred to above, and in particular includeanxiety, depression, pain (especially nociceptive, neuropathic,visceral, post operative pain and pain caused by cancer), pruripus,inflammation, sleep disorders and movement disorders.

Terminology

As used herein, the term “(C_(a)-C_(b))alkyl” wherein a and b areintegers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms. Thus when a is 1 and b is 6, for example, theterm Includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein, the term “(C_(a)-C_(b))fluoroalkyl” wherein a and b areintegers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms in which one or more hydrogen atoms arereplaced by fluorine atoms. Mono- di- and tri-fluoromethyl areencompassed by this term.

As used herein the unqualified term “heteroaryl” refers to a monocyclicor fused bicyclic aromatic radical containing one or more heteroatomsselected from S, N and O. A monocyclic heteroaryl radical may inparticular have 5 or 6 ring atoms. In a fused bicyclic heteroarylradical each fused ring may have 5 or 6 ring atoms. Illustrative ofheteroaryl radicals are thienyl, benzothienyl, furyl, benzofuryl,pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl,isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl;isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl,thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, indolyl and indazolyl.

A divalent phenylene radical is a benzene ring with two unsatisfiedvalencies, and includes 1,3-phenylene and 1,4-phenylene.

A “divalent heteroarylene radical” Is a heteroaryl ring in which tworing carbon atoms have unsatisfied valencies. For example monocyclicdivalent heteroarylene radicals having six ring atoms include thefollowing pyridinylene, pyrimidinylene, and pyrazinylene radicals:

Monocyclic divalent heteroarylene radicals having five ring atomsinclude those of the following formulae:

wherein X is —NH—, —N(CH₃)—, N(CH₂CH₃)—. —O— or —S—, and Y is ═C— or═NH—.

Unless otherwise specified in the context in which it occurs, the term“substituted” as applied to any phenyl or heteroaryl moiety herein meanssubstituted with at least one-substituent, for example selected from(C₁-C₆)alkyl, (C₁-C₆) fluoroalkyl, (C₁-C₆)alkoxy (includingmethylenedioxy and ethylenedioxy substitution on adjacent carbon atomsof an aromatic ring), (C₁-C₆)fluoroalkoxy, (C₁-C₆)alkoxy-(C₁-C₆)alkyl,benzyloxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-(C₁-C₆)alkoxy,benzyloxy-(C₁-C₆)alkoxy, hydroxy, hydroxy(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, mercapto, mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio,cyclopropyl, halo (including fluoro and chloro), nitro, nitrile (cyano),—COOH, tetrazolyl, —COOR^(A), —COR^(A), —SO₂R^(A), —CONH₂, —SO₂NH₂,—CONHR^(A), —SO₂NHR^(A), —CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NH₂,—NHR^(A), —NR^(A)R^(B), —OCONH₂, —OCONHR^(A), —OCONR^(A)R^(B),—NHCOR^(A), —NHCOOR^(A), —NR^(B)COOR^(A), —NHSO₂OR^(A),—NR^(B)SO₂OR^(A), —NHCONH₂, —NR^(A)CONH₂, —NHCONHR^(B),—NR^(A)CONHR^(B), —NHCONR^(A)R^(B), or —NR^(A)CONR^(A)R^(B) whereinR^(A) and R^(B) are independently a (C₁-C₄)alkyl group, or R^(A) andR^(B) when attached to the same nitrogen may form, together with thatnitrogen, a cyclic amino group such as a morpholinyl, piperidinyl orpiperazinyl group. An “optional substituent” may be one of thesubstituent groups encompassed in the above description.

As used herein the term “salt” includes base addition, acid addition andquaternary salts. Compounds of the invention which are acidic can formsalts, including pharmaceutically or veterinarily acceptable salts, withbases such as alkali metal hydroxides, e.g. sodium and potassiumhydroxides; alkaline earth metal hydroxides e.g. calcium, barium andmagnesium hydroxides; with organic bases e.g. N-ethyl piperidine,dibenzylamine and the like. Those compounds (I) which are basic can formsalts, including pharmaceutically or veterinarily acceptable salts withinorganic acids, e.g. with hydrohalic acids such as hydrochloric orhydrobromic acids, sulphuric acid, nitric acid or phosphoric acid andthe like, and with organic acids e.g. with acetic, tartaric, succinic,fumaric, maleic, malic, salicylic, citric, methanesulphonic andp-toluene sulphonic acids and the like. Any unqualified reference hereinto a compound which falls within formula (I) is to be construed as areference to that compound, irrespective of whether it is or is not inthe form of salt.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

In common with many organic compounds useful in medicine, at least someof the compounds of the invention are expected to be recoverable ascrystalline hydrates and solvates. Such hydrates and solvates are ofcourse merely specific physico-chemical forms of the active compounds ofthe invention and therefore form part of the invention-. Any unqualifiedreference herein to a compound which falls within formula (I) is to beconstrued as a reference to that compound, irrespective of whether it isor is not in the form of a hydrate or solvate. The term ‘solvate’ isused herein to describe a molecular complex comprising the compound ofthe invention and a stoichiometric amount of one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

Structural Features

In the compounds of the invention:

Ar¹ may be optionally substituted phenyl, or may be selected from thegroup of monocyclic heteroaryl groups consisting of, for example,pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl,thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, andtriazinyl, any of which being optionally substituted. In particularcases, Ar¹ is phenyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,[1,3,4]thiadiazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,2,3]oxadiazol-4-yl,1-, 4-pyrazolyl, or [1,2,4]triazol-3-yl, any of which being optionallysubstituted. In specific cases, Ar¹ may be, for example, phenyl,2-fluorophenyl, 3-(2-methoxy-ethoxy)-phenyl, or2-methoxy-5-(2-methoxy-ethoxy)-phenyl.

Ar² may be optionally substituted phenyl; or may be selected from thegroup of monocyclic heteroaryl groups consisting of, for example,pyridyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazoyl, triazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, any of which beingoptionally substituted; or may be selected from the group of fusedbicyclic heteroaryl groups consisting of, for example, benzothienyl,benzofuryl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, pyrazolyl,benzoxazolyl, benzisoxazolyl, benztriazolyl, indoyl and indazolyl, anyof which being optionally substituted. In particular cases, Ar² isphenyl, 2-, 3- or 4-pyridyl, 2-, 4 or 5-pyrimidinyl, pyrazin-2-yl,pyridazin-3-yl, 2-thiazolyl, 2-oxazolyl, benz[d]isoxazol-3-yl,indazol-3-yl, 5-oxadiazolyl, or 5-thiadiazolyl, any of which beingoptionally substituted.

Currently preferred Ar² groups include phenyl, pyridyl, pyrimidinyl,pyrazinyl or pyridazinyl; any of which being optionally substituted. Forexample, Ar² may be 3-pyridyl, pyrimidin-4-yl, pyrazin-2-yl orpyridazin-3-yl.

Ar³ may be an optionally substituted phenylene radical, such as; forexample, a 1,4-phenylene radical; or may be selected from the groupconsisting of, for example, divalent pyridinylene, thienylene, furylene,pyrrolylene, imidazolylene, oxazolylene, isoxazolylene, thiazolylene,isothiazolylene, pyrazolylene, triazolylene, pyridazinylene,pyrimidinylene, pyrazinylene, triazinylene, thiadiazolylene radicals,any of which being optionally substituted.

Currently preferred Ar³ radicals include phenylene or pyridinyleneradical, such as an optionally substituted divalent 1,4-phenylene or a2,5-pyridinylene radical of formula:

wherein the bond marked with a single asterisk is attached to Ar¹ andthe bond marked with a double asterisk is attached to the oxygen shownin Formula (I).

Other specific examples of heteroarylene Ar¹ radicals include thefollowing group of divalent radicals, any of which being optionallysubstituted:

wherein the bond marked with a single asterisk is attached to Ar¹ andthe bond marked with a double asterisk is attached to the oxygen.

Usually, no more than two optional substituents per ring will be presentin Ar¹, Ar² and Ar³. Any optional substituents in Ar¹, Ar² and Ar³ maybe independently selected from, for example, chloro, fluoro, bromo,cyclopropyl, methyl, mono-, di- or tri-methyl, trifluoromethyl,difluoromethyl, monofluoromethyl, methoxy, ethoxy, propoxy, butoxy,pentoxy, 2-methoxyethoxy, 2-benzyloxy-ethoxy, 2-hydroxy-ethoxy, mono-,di- or tri-fluoromethoxy, cyano, hydroxy. —CO₂R₁ or —SO₂R₁ wherein R₁ ishydrogen, methyl or ethyl, tetrazolyl, —NR₂R₃, —CH₂NR₂R₃ and —C(═O)NR₂R₃wherein R₂ and R₃ are independently hydrogen, methyl or ethyl.

In some compounds of the invention the radical Ar¹—Ar³— is4-phenylphenyl, for example a biphenyl-4-yl radical.

In other compounds of the invention, Ar² is 2- or 3-fluorophenyl, or3-pyridyl.

In a currently preferred subclass of compounds of the invention:

-   -   Ar² is 3-pyridyl, pyrimidin-4-yl, pyrazin-2-yl or        pyridazin-3-yl;    -   Ar³ is an optionally substituted divalent 1,4-phenylene or a        2,5-pyridinylene radical of formula:

-   -   wherein the bond marked with a single asterisk is attached to        Ar¹ and the bond marked with a double asterisk is attached to        the oxygen; and    -   Ar¹ is optionally substituted phenyl.

In that preferred subclass. Ar¹ may be, for example, 2-fluorophenyl,3-(2-methoxy-ethoxy)-phenyl, or 2-methoxy-5-(2-methoxy-ethoxy)-phenyl,and it is currently preferred that Ar² be pyridazin-3-yl;

Specific examples of compounds of the invention include those of theExamples herein.

Compounds of the invention which are currently preferred for theircombination of good intrinsic FAAH inhibitory potency, and high andprolonged plasma concentrations after oral administration, as evidencedin tests in laboratory rats, are

-   3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid pyridin-3-ylamide;-   3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid    pyridazin-3-ylamide;-   3-{5-[3-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic    acid pyridazin-3-ylamide;-   3-(5-phenyl-pyridin-2-yloxy)-azetidine-1-carboxylic acid    pyridazin-3-ylamide;-   3-[5-(2-methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid    pyridazin-3-ylamide;    and pharmaceutically acceptable salts thereof.

Synthesis

There are multiple synthetic strategies for the synthesis of thecompounds (I) with which the present invention is concerned, but allrely on known chemistry, known to the synthetic organic chemist. Thus,compounds according to formula (I) can be synthesised according toprocedures described in the standard literature and are well-known toone skilled in the art. Typical literature sources are “Advanced organicchemistry”, 4^(th) Edition (Wiley), J March, “Comprehensive OrganicTransformation”, 2^(nd) Edition (Wiley), R. C. Larock, “Handbook ofHeterocyclic Chemistry”, 2^(nd) Edition (Pergamon), A. R. Katritzky),review articles such as found in “Synthesis”, “Acc. Chem. Res.”, “Chem.Rev”, or primary literature sources identified by standard literaturesearches online or from secondary sources such as “Chemical Abstracts”or “Beilstein”. Such literature methods include those of the preparativeExamples herein, and methods analogous thereto.

For example, an azetidine of formula (II) or a salt thereof may bereacted with an isocyanate of formula (III) to provide compounds of theinvention. Any reactive optional substituents in Ar¹, Ar² or Ar¹ may beprotected during the reaction and deprotected thereafter:

Other synthetic routes to compounds of the invention are summarized inSchemes 1, 2 and 3 of the Examples below.

Utilities

As stated above, the compounds of the Invention are useful in thetreatment of diseases or medical conditions which benefit frominhibition of FAAH activity, and examples of such diseases andconditions have been mentioned above.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the causative mechanism and severity ofthe particular disease undergoing therapy. In general, a suitable dosefor orally administrable formulations will usually be in the range of0.1 to 3000 mg, once, twice or three times per day, or the equivalentdaily amount administered by injection, inhalation, infusion or otherroutes. However, optimum dose levels and frequency of dosing will bedetermined by clinical trials as is conventional in the art.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations. Tablets and capsules for oral administration may be inunit dose presentation form, and may contain conventional excipientssuch as binding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. Other particularformulations for oral administration include chewing gums, and suckablelozenges and lollipops, containing the compound of the invention.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia. Methods of delivery via sustained releasepatches for application to the skin are also known in the art.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

The active ingredient may also be formulated for inhalation, for exampleas a nasal spray, or dry powder or aerosol inhalers. For delivery byinhalation, the active compound is preferably in the form ofmicroparticles. They may be prepared by a variety of techniques,including spray-drying, freeze-drying and micronisation. Aerosolgeneration can be carried out using, for example, pressure-driven jetatomizers or ultrasonic atomizers, preferably using propellant-drivenmetered aerosols or propellant-free administration of micronized activecompounds from, for example, inhalation capsules or other “dry powder”delivery systems.

Compounds of the invention may be administered together with otherclasses of pharmaceutically active drugs.

The following examples illustrate the preparation and activities ofspecific compounds of the invention and are not intended to be limitingof the full scope of the invention.

Part A: Examples 1-4

¹H (400 MHz) and ¹³C (100 MHz) Nuclear magnetic resonance (NMR) analysiswas performed using a Bruker DPX-400 MHz NMR spectrometer. The spectralreference was the known chemical shift of the sample solvent. ¹H nmrdata is reported indicating the chemical shift (δ), the multiplicity (s,singlet; d, doublet; t, triplet q, quartet; m, multiplet; dd, doublet ofdoublets; br, broad; app, apparent etc.), the integration (e.g. 1H), thecoupling constant(s) (J) in Hz. ¹³C data is reported indicating thechemical shift (□). Deuterated solvents were obtained from theSigma-Aldrich Chemical Company or Fluorochem.

LCMS analyses were performed on a HP1100 instrument, with a Luna 3 μM,C18(2), 30 mm×4.6 mm i.d. column from Phenomenex at a temperature of 22°C., at a flow rate of 2 mL min⁻¹ using the following solvent systems:

-   -   Solvent A: HPLC grade Water+10 mM ammonium acetate+0.08% v/v        formic add.    -   Solvent B: 95% v/v HPLC grade acetonitrile+5% v/v Solvent        A+0.08% v/v formic acid.    -   Gradient 95:5 Solvent A:Solvent B, 0.00 to 0.25 mins.; 95:5 to        5:95 Solvent A:Solvent B, 0.25 to 2.50 mins.; 5:95 Solvent        A:Solvent B, 2.50 to 3.75 mins.

UV detection was at 230 nm, 254 nm and 270 nm. Mass spectrometer was aHP1100MSD, Series A instrument, operating in positive or negative ionelectrospray ionisation mode. Molecular weight scan range is 120 to1000. Samples were supplied as a 1 mM solution in DMSO, with 5 μLpartial loop fill injection.

Preparative HPLC purifications were performed on a Waters FractionLynxMS Autopurification system with a Gemini® 5 μM C18(2), 100 mm×20 mm i.d.column from Phenomenex, running at a flow rate of 20 mL min⁻¹ with UVdiode array detection (210-400 nm) and mass-directed collection.Gradients used for each compound are shown in Table 1. Solvents A and Bare as for the analytical conditions above. The mass spectrometer was aWaters Micromass ZQ2000 spectrometer operating in positive or negativeion electrospray ionisation modes, with a molecular weight scan range of150 to 1000.

Example 1: 3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid phenylamide

Step 1 1-Benzhydryl-3-biphenyl-4-yloxy)azetidine

4-Phenylphenol (8.51 g, 50 mmol), 1-benzhydrylazetidin-3-ol (11.97 g, 50mmol) and triphenylphosphine (13.11 g, 50 mmol) were stirred inacetonitrile (250 mL) for 20 minutes at room temperature, until al thereagents were fully dissolved. Diisopropyl Azodicarboxylate (9.84 mL,10.11 g, 50 mmol) was added dropwise. A white precipitate forms and theinitial reaction is mildly exothermic. The yellow colour is immediatelydischarged. After 5 minutes, the reaction is heated to refluxtemperature, whereupon the precipitate dissolved, and stirred at thistemperature for 3.25 hours. The mixture was cooled to room temperature,and scratched with a spatula to induce crystallisation. The mixture wascooled on ice, and the solids collected by filtration. The solids werewashed with further cold acetonitrile and dried thoroughly to give theether (15.42 g, 79%) as a white powder; mp 141-142° C.; R_(f) 0.68 (2:1hexane:EtOAc); LCMS retention time 2.57 mins, m/z 392.2 [M+H]; ¹H nmr(400 MHz; DMSO-ds) δ 7.60-7.52 (m, 4H), 7.46-7.39 (m, 6H), 7.31-7.26 (m,5H), 7.19 (tt, 2H, J=7.2 and 2.0 Hz), 6.90 (d, 2H, J=8.8 Hz), 4.88 (appqn, 1H, J=5.6 Hz), 4.53 (s, 1H), 3.67-3.63 (m, 2H) and 3.02-2.98 (m,2H).

Step 2 3-(biphenyl-4-yloxy)azetidine hydrochloride

1-Benzhydryl-3-(biphenyl-4-yloxy)azetidine (15.40 g, 39.34 mmol) wasdissolved in dichloromethane (400 mL), stirred, and cooled in anice-water bath. 1-Chloroethyl chloroformate (8.49 mL, 11.25 g, 78.69mmol) was added in 1 mL portions over 10 minutes, and the mixturestirred for a further 30 minutes at 0° C., then at rt for 25.5 hours.Further 1-chloroethyl chloroformate (4.25 mL, 5.63 g, 39.35 mmol) wasadded and the mixture stirred for 3 days. The solvents were evaporatedin vacuo and methanol (300 mL) added to the resulting white solid. Themixture was heated gently to dissolve, and then allowed to cool whilststirring vigorously, whereupon a white precipitate formed. After afurther 2 hours stirring at room temperature, the solids where collectedby filtration to give the amine (7.41 g, 72%) as a white solid; mp>195°C.; LCMS retention time 1.64 mins, m/z 226.1 [M+H]⁺; ¹H nmr (400 MHz;DMSO-d₆) δ 9.26 (br s, 2H), 7.64-7.60 (m, 4H), 7.47-7.41 (m, 2H), 7.33(tt, 1H, J=7.3 and 1.2 Hz), 6.96 (d, 2H, J=8.8 Hz). 5.13 (tt, 1H, J=6.8and 4.8 Hz), 4.46 (dd, 2H, J=12.4 and 6.8 Hz) and 4.01 (dd, 2H, J=12.4and 4.8 Hz).

Step 3: 3-(biphenyl-4-yloxy)-azetidine-1-carboxylic acid phenylamide

To a stirred suspension of 3-(1,1′-biphenyl-4-yloxy)azetidinehydrochloride (100 mg, 382 μmol) in dichloromethane (2.5 mL) was addedtriethylamine (63 μL, 48 mg, 478 μmol) followed by phenyl isocyanate (35μL, 38 mg, 320 μmol) and the reaction stirred at room temperature for2.5 hours. The mixture was loaded directly onto a 2 g pre-packed SCX-2cartridge and the product eluted with 1:1 dichloromethane:methanol (15mL). The solvents were evaporated to give the urea (113 mg, 100%) as awhite powder, LCMS retention time 2.57 minutes, m/z 345.2 [M+H]⁺; ¹H nmr(400 MHz; DMSO-d_(d)) δ 8.54 (s, 1H), 7.62 (d, 4H, J=7.6 Hz), 7.50 (d,2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.23 (t,2H, J=7.8 Hz), 7.98-7.91 (m, 3H), 5.09 (m, 1H), 0.4.46-4.42 (m, 2H) and3.95-3.91 (m, 2H).

Example 2: 3-(Biphenyl-4-yloxy)-azetidine-1-carboxylic acid(3-fluoro-phenyl)-amide

The title compound was prepared as for Example 1, using 3-fluorophenylisocyanate in place of phenyl isocyanate. The product was obtained as awhite powder; LCMS retention time 2.61 minutes, m/z 363.1 [M+H]; ¹H nmr(400 MHz; DMSO-d₆) δ 8.76 (s, 1H), 7.64-7.61 (m, 4H), 7.51-7.41 (m, 3H),7.34-7.23 (m, 3H), 6.96 (d, 2H, J=8.4 Hz), 6.77-6.72 (m, 1H), 5.12-5.07(m, 1H), 4.46 (dd, 2H, J=9.2 and 6.4 Hz) and 3.94 (dd, 2H, J=9.2 and 4.0Hz).

Example 3: 3-(Biphenyl-4-yloxy)azetidine-1-carboxylic acid(2-fluoro-phenyl)-amide

The title compound was prepared as for Example 1, using 2-fluorophenylisocyanate in place of phenyl isocyanate. The product was purified bytrituration with diethyl ether to give the title compound as anoff-white solid; LCMS retention time 2.60 minutes, m/z 363.1 [M+H]⁺; ¹Hnmr (400 MHz; DMSO-ds) 8.33 (s, 1H), 7.64-7.58 (m, 5H), 7.44 (t, 2H,J=7.6 Hz), 7.32 (t, 1H, J=7.4 Hz), 7.23-7.17 (m, 1H), 7.14-7.08 (m, 2H),6.96 (d, 2H, J=8.8 Hz), 5.13-5.07 (m, 1H), 4.45 (dd, 2H, J=9.2 and 6.8Hz) and 3.94 (dd, 2H, J=9.2 and 3.6 Hz).

Example 4: 3-(Biphenyl-4-yloxy)-azetidine-1-carboxylic acidpyridin-3-ylamide

3-(Biphenyl-4-yloxy)azetidine hydrochloride (3 g, 11.47 mmol) wassuspended in dichloromethane (45 mL) under a nitrogen atmosphere,treated with triethylamine (4.0 mL, 28.68 mmol) and stirred for 10minutes at room temperature. The mixture was cooled to 0° C. and treatedportionwise with pyridine-3-isocyanate (1.15 g, 9.56 mmol). Stirred at0° C. for 10 minutes, then at rt for 16 hours. The solution was dilutedwith further dichloromethane (200 mL), washed with H₂O (2×100 mL),followed by brine (50 mL), dried (over MgSO₄), and solvent evaporated invacuo to yield an off-white solid. The solid was triturated with diethylether, then stirred for 3 days with MP-isocyanate resin in adichloromethane/methanol/acetonitrile mixture. The mixture was filteredand reduced to dryness in vacuo. The resulting solid was trituratedsuccessively with diethyl ether, then acetonitrile and filtered to givethe urea (1.2 g, 36%) as a white solid; R_(f) 0.10 (5% MeOH-DCM); LCMSretention time 2.08 minutes, m/z 346.2 [M+H]⁺; ¹H nmr (400 MHz; DMSO-d)δ 8.97 (s, 1H), 8.75 (d, 1H, J=2.3 Hz), 8.21 (d, 1H, J=4.7 Hz),8.05-8.01 (m, 1H), 7.65-7.60 (m, 4H), 7.44 (t, 2H, J=7.9 Hz), 7.39 (dd,1H, J=8.3 and 4.7 Hz), 7.32 (t, 1H, J=7.3 Hz), 6.96 (d, 2H, J=8.8 Hz),5.14-5.08 (m, 1H), 4.49 (dd, 2H, J=9.5 and 6.5 Hz) and 3.97 (dd, 2H,J=9.5 and 3.8 Hz); ¹³C nmr (100 MHz; DMSO-ds) 156.2 (C), 155.9 (C),141.4 (CH), 139.6 (C), 138.9 (CH), 137.3 (C), 133.4 (C), 128.9 (CH),128.1 (CH), 126.9 (CH), 126.8 (CH), 126.3 (CH), 123.9 (CH), 115.1 (CH),65.6 (CH) and 56.4 (CH₂).

Part B—Examples 5-19 General Procedures

All reagents obtained from commercial sources were used without furtherpurification. Anhydrous solvents were obtained from commercial sourcesand used without further drying. Flash chromatography was performed withpre-packed silica gel cartridges (Strata SI-1; 61 Å, Phenomenex,Cheshire UK or IST Flash II, 54 Å, Argonaut, Hengoed, UK). Thin layerchromatography (TLC) was conducted with 5×10 cm plates coated with MerckType 60 F₂₅₄ silica gel. Once visible under UV, the retention factor(R_(f)) value of each spot could be determined if appropriate bydividing the distance traveled by the product by the total distancetraveled by the solvent (the solvent front).

Some compounds of the present invention were characterized by LC/MS(Method A) using a Hewlett Packard 1100 series LC/MSD linked toquadripole detector (ionization mode:electron spray positive ornegative; column: Phenomenex Luna 3 &M C18(2) 30×4.6 mm at 22° C. BufferA prepared by dissolving 1.93 g ammonium acetate in 2.5 L HPLC grade H₂Oand adding 2 mL formic acid. Buffer B prepared by adding 132 mL buffer Ato 2.5 L of HPLC grade acetonitrile and adding 2 mL formic acid; elutiongradient 95:5 to 5:95 buffer A:buffer B over 3.75 minutes. (Injectionvolume: 2 μl). Flow rate=2.0 mL/min. UV detection was by diode arraydetector at 230, 254 and 270 nm. Retention Times (RT) are reported inminutes. Ionisation is positive unless otherwise stated.

Some compounds of the present invention were characterised by analternative LC/MS method (“Method B”) using an Agilent 1200 SL seriesinstrument connected to an Agilent MSD 6140 single quadrupole with amultimode source; column: Phenomenex Luna 2.5 μM C18, 50×2 mm, HST at55° C. column temperature. Buffer A: Water/10 mM ammonium formate/0.04%(v/v) formic acid pH=3.5. Buffer B: Acetonitrile/5.3% (v/v) A/0.04%(v/v) formic. Gradients and flow rates for method B are shown in Table 1(Injection volume: 2 μL). UV detection was by diode array detector at230, 254 and 270 nm. Retention Times (RT) are reported in minutes.Ionisation is positive unless otherwise stated.

TABLE 1 Solvent Gradients and Flow rates for LC/MS Method B. Time (min)Solvent A (%) Solvent B (%) Flow (mL/min) 0.00 95 5 1.1 0.12 95 5 1.11.30 5 95 1.1 1.35 5 95 1.7 1.85 5 95 1.7 1.90 5 95 1.1 1.95 95 5 1.1

Nuclear magnetic resonance (NMR) analysis was performed with a BruckerDPX-400 MHz NMR spectrometer. The spectral reference was the knownchemical shift of the solvent. Proton NMR data is reported as follows:chemical shift (8) in ppm, multiplicity (s=singlet, d=doublet,t=triplet, q=quartet, p=pentet, m=multiplet, dd=doublet of doublet,br=broad), integration, coupling constant.

Some compounds of the invention were purified by preparative HPLC.Preparative HPLC purifications were performed on a Waters FractionLynxMS Autopurification system with a Gemini® 5 μM C18(2), 100 mm×20 mm i.d.column from Phenomenex, running at a flow rate of 20 mL min⁻¹ with UVdiode array detection (210-400 nm) and mass-directed collection.Appropriate solvents gradients for compound elution were determined foreach particular compound.

At pH 4: Solvent A: HPLC grade Water+10 mM ammonium acetate+0.08% v/vformic acid.

Solvent B: 95% v/v HPLC grade acetonitrile+5% v/v Solvent A+0.08% v/vformic acid.

At pH 9: Solvent A: HPLC grade Water+10 mM ammonium acetate+0.08% v/vammonia solution.

Solvent B: 95% v/v HPLC grade acetonitrile+5% v/v Solvent A+0.08% v/vammonia solution.

¹H (400 MHz) and ¹³C (100 MHz) Nuclear magnetic resonance (NMR) analysiswas performed using a Bruker DPX-400 MHz NMR spectrometer. The spectralreference was the known chemical shift of the sample solvent. ¹H nmrdata is reported indicating the chemical shift (6), the multiplicity (s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doubletof doublets; br, broad; app, apparent etc.), the Integration (e.g. 1H),the coupling constant(s) (J) in Hz. ¹³C data is reported indicating thechemical shift (□). Deuterated solvents were obtained from theSigma-Aldrich Chemical Company or Fluorochem.

The mass spectrometer was a Waters Micromass ZQ2000 spectrometeroperating in positive or negative ion electrospray ionisation modes,with a molecular weight scan range of 150 to 1000.

IUPAC chemical names were generated using AutoNom Standard.

Some compounds of the Examples were made by the route outlined in scheme1.

Some compounds of the Examples were made by the route outlined in scheme2.

Some compounds of the Examples were made by the route outlined in scheme3. Experimental methods, reagents and product isolation methods will beknown to those skilled in the art of organic synthesis. It is understoodthat other methods can also be used.

Example 53-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyrimidin-4-ylamide

Step 1 2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine

Sodium Hydride (60 wt % dispersion in mineral oil, 6.36 g, 0.156 mol)was added in portions to a solution of 1-benzhydryl-azetidin-3-ol (25.38g, 0.106 mol) in anhydrous dimethylformamide (400 mL) under a Nitrogenatmosphere. This caused a precipitate to form and effervescence tooccur. When addition was complete the reaction mixture was stirred atambient temperature for 15 min. A solution of 2-chloro-5-iodopyridine(25.40 g, 0.106 mol) in dimethylformamide (100 mL) was added to thereaction mixture via a dropping funnel over 15 minutes. When additionwas complete the reaction mixture was heated to 70° C. and stirred,under nitrogen atmosphere, for 4.5 hr. Reaction mixture was then allowedto cool to ambient temperature and a sat. aqueous ammonium chloridesolution (30 mL) was added. The solvents were removed in vacuo and theresidual solid was partitioned between ethyl acetate (600 mL) and sat.aqueous sodium bicarbonate solution (500 mL). The phases were separatedand the organic phase was washed with sat. aqueous sodium chloridesolution (3×300 mL), dried over sodium sulphate, filtered and filtratesolvents removed in vacuo to afford a yellow-brown solid which wastriturated with diethyl ether, filtered and dried in vacuo to afford thetitle compound as a beige-coloured solid (33.41 g, 71%) LCMS (Method A)RT=2.19 min; m/z=443 [M+H]⁺

Step 2 2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride

1-chloroethyl chloroformate (12.8 mL, 0.104 mol) was added drop-wise viasyringe to a stirred solution of2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (23.03 g, 0.052 mol)In dichloromethane (250 mL) at ambient temperature. The resultingsolution was stirred at ambient temperature for 3.5 hr. then methanol(250 mL) was added and the reaction mixture stirred at ambienttemperature for 16 hr. The solvents were then removed in vacuo and theresulting solid residue was triturated with diethyl ether, filtered andthen dried in vacuo to afford the title product as a cream-colouredsolid (17.8 g, >quant yield). The crude product was used directlywithout further purification.

LCMS (Method A) RT=1.24 min; m/z=277 [M+H]⁺

Step 3 Intermediate 5 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylicacid 4-nitro-phenyl ester

4-nitrophenyl chloroformate (692 mg g, 3.44 mmol) was added to a stirredsolution of 2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (1.01 g,2.29 mol) in dichloromethane (40 mL) at ambient temperature. Theresulting solution was stirred at ambient temperature for 18 hr. Thesolvent was removed in vacuo and the product purified by flashchromatography on silica gel (25 g) eluting with dichloromethane toafford the title compound as a colourless solid (474 mg, 47%).

LCMS (Method A) RT=2.54 min; m/z=442 [M+H]⁺. ¹H NMR: (400 MHz, DMSO-d₆)δ 3.95-4.04 (m, 1H, 4.16-4.24 (m. 1H), 4.36-4.44 (m, 1H), 4.56-4.74 (m.1H), 5.35-5.40 *m. 1H), 6.84 (d, 1H, J=8.5 Hz). 7.43-7.47 (m, 2H), 8.07(dd, 1H, J=8.5, 2.2 Hz), 8.26-8.29 (m, 2H), 8.38 (d, 1H, J=2.1 Hz).

Step 4 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrimidin-4-ylamide

A solution of 4-aminopyrimidine (Aldrich, 243 mg, 2.54 mmol) inanhydrous DMF (4 mL) was added via syringe to a suspension of sodiumhydride (60 wt % dispersion in mineral oil, 185 mg, 4.62 mmol) inanhydrous DMF (4 mL) under a nitrogen atmosphere. The mixture wasstirred for 5 min. then a solution of3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenylester (1.02 g, 2.31 mmol) in anhydrous DMF (6 mL) was added drop-wiseand the resulting yellow coloured turbid mixture was stirred at ambienttemperature for 1.5 hr. The reaction mixture was poured into sat.aqueous ammonium chloride solution (30 mL) and extracted with ethylacetate (3×100 mL). The combined organic phases were washed with sat.aqueous sodium chloride solution (100 mL) and dried over sodiumsulphate. The mixture was filtered and the filtrate solvents removed invacuo to afford a yellow solid, which was triturated with diethyl ether,filtered and dried to afford the title compound (594 mg, 65%) as acolourless solid.

LCMS (Method A) RT=1.89 min; m/z=398 [M+H]⁺.

Step 52-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Potassium carbonate (1.88 g, 13.65 mmol) was added to a solution of3-hydroxyphenylboronic acid pinacol ester (Apollo, 1.0 g, 4.55 mmol) inDMF (10 mL). 2-Bromoethyl methyl ether (0.41 mL, 5.46 mmol) was addedand the reaction mixture was heated to 100° C. for 1 hr. The reactionmixture was allowed to cool and then partitioned between ethyl acetate(50 mL), and water (150 mL). The phases were separated and the organicphase was washed with brine (150 mL), dried over anhydrous sodiumsulphate, filtered and the filtrate solvents removed in vacuo, to affordthe title product as a light-brown oil (1.1 g) which was used withoutfurther purification.

LCMS (Method A) RT=1.42 min; m/z=no ionisation.

Step 63-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyrimidin-4-ylamide

A solution of2-[3-(2-Methoxy-ethoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(Step 5, 109 mg, 0.39 mmol) in THF/H₂O (10:1; 3 mL) was added to amicrowave vial containing3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrimidin-4-ylamide (step 4, 104 mg, 0.26 mmol) and potassium carbonate(108 mg, 0.786 mmol). Nitrogen gas was bubbled through the mixture for 5mins then 1,1′-bis((diphenylphosphino)-ferrocene)dichloropalladium(II)complex with CH₂Cl₂ (21 mg, 10 mole %) was added and the vial sealed andheated at 100° C. in microwave synthesiser for 30 min. The cooledreaction mixture was diluted with ethyl acetate (20 mL) and washedthrough celite (2.5 g IST cartridge). A further 10 mL of ethyl acetatewas washed through the celite pad and combined filtrate was washedsequentially with water (30 mL). IN NaOH solution (30 mL), water (30 mL)then sat. sodium chloride solution (30 mL). Mixture dried over sodiumsulphate and filtered. Filtrate solvents were removed in vacuo to afforda brown gum, which was purified by flash chromatography, eluting with agradient of 50 to 100% ethyl acetate in hexane to a afford a gummysolid. Product was dissolved in dichloromethane (25 mL) and 2N NaOH (aq,25 mL) was added and mixture stirred vigorously for 1 h. Phases wereseparated and the organic layer dried over sodium sulphate, filtered andfiltrate solvent removed in vacuo to leave a solid, which was trituratedwith diethyl ether, filtered and dried to afford the title compound ascolourless solid (50 mg, 45%)

LCMS: (Method A) RT=1.97 min; m/z=422 [M+H]⁺.

TLC: R_(f)=0.39 (100% EtOAc). ¹H NMR: (400 MHz, DMSO-d₆) δ 3.32 (s, 3H),3.68 (m; 2H), 4.03 (brm, 2H), 4.17 (m, 2H), 4.48 (brm, 2H), 5.38 (m,1H), 6.95 (dd, 1H, J=8.1, 2.5 Hz), 6.99 (d, 1H, J=8.6 Hz), 7.20-7.26 (m,2H), 7.37 (dd, 1H, J=8.3, 8.3 Hz), 7.92 (dd, 1H, J=5.7, 1.2 Hz), 8.08(dd, 1H, J=8.6, 2.5 Hz), 8.48-8.54 (m, 2H), 8.57 (m, 1H), 9.86 (brs,1H).

Example 63-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyrazin-2-ylamide

Step 1 2-(1-Benzhydryl-azetidin-3-yloxy)-5-bromo-pyridine

This compound was prepared by the method outlined for example 5 step 1.Thus 5-bromo-2-chloropyridine (31.31 g, 0.163 mol) and1-benzhydryl-azetidin-3-ol (38.92 g, 0.163 mol) were reacted to affordtitle compound (44.14 g, 64%) as light brown solid.

LCMS: (Method A) RT=2.11 min; m/z=397 [M+H]⁺.

Step 2 2-(Azetidin-3-yloxy)-5-bromo-pyridine hydrochloride

This compound was prepared by the method outlined for example 5 step 2.Thus 2-(Azetidin-3-yloxy)-5-bromo-pyridine hydrochloride (13.76 g, 0.035mole) was reacted with 1-chloroethyl chloroformate to afford titlecompound (10.22 g>quant. yield) as a brown solid.

LCMS: (Method A) RT=1.15 min; m/z=231 [M+H]⁺.

Step 3 3-(5-Bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid4-nitro-phenyl ester

This compound was prepared by the method outlined for example 5 step 3.Thus 2-(Azetidin-3-yloxy)-5-bromo-pyridine hydrochloride (2.0 g, 7.53mmol) was reacted with 4-nitrophenyl chloroformate to afford the titlecompound (1.11 g, 37%) as a pale-yellow solid.

LCMS: (Method A) RT=2.50 min; m/z=396 [M+H]⁺.

Step 4 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrazin-2-ylamide

This compound was prepared by the method outlined for example 5 step 4.Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid4-nitro-phenyl ester (905 mg, 2.30 mmol) was reacted with2-aminopyrazine (243 mg, 2.53 mmol) to afford the title compound (454mg, 56%) as off white solid.

LCMS: (Method A) RT=1.86 min; m/z=352 [M+H].

Step 53-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyrazin-2-ylamlde

This compound was prepared by the method outlined for example 5 step 6.Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrazin-2-ylamide (100 mg, 0.285 mmol) was reacted with2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(example 5 step 5, 118 mg, 0.855 mmol) to afford title compound (70 mg,58%) as a colourless powder.

LCMS: (Method A) RT=2.01 min; m/z=422 [M+H]⁺.

TLC: R_(f)=0.51 (100% EtOAc)

¹H NMR: (400 MHz, DMSO-d₆) δ 3.32 (s, 3H), 3.68 (m, 2H), 4.03 (m, 2H),4.17 (m, 2H), 4.48 (m, 2H), 5.39 (m, 1H), 6.95 (m, 1H), 6.99 (d, 1H,J=8.6 Hz), 7.21-7.25 (m, 2H), 7.37 (dd, 1H, J=8.3, 8.3 Hz), 8.09 (dd,1H, J=8.5, 2.5 Hz), 8.22 (d, 1H, J=2.5 Hz), 8.29 (m, 1H) 8.49 (d, 1H,J=2.0 Hz), 9.17 (d, 1H, J=1.5 Hz), 9.65 (brs, 1H).

Example 73-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

Step 1 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide

To an ice-bath cooled solution of sodium hydride (60 wt % in mineraloil, (2.1 g. 52.4 mmol) in DMF (50 mL) under nitrogen atmosphere wasadded (dropwise) a solution of 3-aminopyridazine (2.74 g, 28.79 mmol) inDMF (50 mL). After several minute a solution of3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitrophenylester (Example 5, step 3); 11.54 g, 26.18 mmol) in DMF (40 mL) wasadded. After 5 min the cooling bath was removed and reaction allowed towarm to ambient temperature and stir for 1.5 hr. Saturated sodiumbicarbonate solution (500 mL) was added and the mixture was extractedwith EtOAc (4×400 mL). Combined organic phases were washed with satsodium chloride solution (500 mL), dried over sodium sulphate andfiltered. The filtrate solvents were removed in vacuo to afford a crudeproduct that was triturated with diethyl ether to afford the titlecompound (7.52 g, 72%) as a colourless solid.

LCMS: (Method A) RT=1.84 min; m/z=398 [M+H]⁺.

Step 23-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

This compound was prepared in similar fashion to the method outlined forExample 5 step 6. Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylicacid pyridazin-3-ylamide (456 mg, 1.15 mmol) was reacted with2-[3-(2-Methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(example 5 step 5, 392 mg, 1.50 mmol) to afford title compound (120 mg,25%) as a colourless powder.

LCMS: (Method A) RT=1.18 min; m/z=422 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.32 (s, 3H), 3.68 (m, 2H), 4.04 (brm, 2H),4.17 (m, 2H), 4.49 (brm, 2H), 5.40 (m, 1H), 6.95 (m, 1H), 6.99 (d, 1H,J=8.9 Hz), 7.21-7.25 (m, 2H), 7.37 (dd, 1H, J=8.3, 8.3 Hz), 7.59 (dd,1H, J=9.1, 4.5 Hz), 8.09 (dd, 1H, J=8.6, 2.6 Hz), 8.15 (dd, 1H, J=9.1,1.4 Hz), 8.50 (d, 1H, J=4.5, 1.4 Hz), 8.85 (dd, 1H, J=4.5, 1.4 Hz), 9.97(s, 1H).

Example 83-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridin-3-ylamide

Step 1 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridin-3-ylamide

2-(Azetidin-3-yloxy)-5-iodo-pyridine hydrochloride (4.2 g, 13 mmol) wassuspended in anhydrous dichloromethane (50 mL) and triethylamine (5.5mL) was added. Pyridine-3-isocyanate (1.45 g, 11.7 mmol) was added andthe reaction mixture was stirred at ambient temperature for 16 hr. Thesuspension solvents were removed in vacuo and the residue partitionedbetween ethyl acetate (400 mL) and sat. aqueous sodium bicarbonatesolution (400 mL). The mixture was filtered through a pad of celite andthe filtrate phases were separated. The organic phase was washed withsat. aqueous sodium bicarbonate solution (250 mL), then sat aqueoussodium chloride solution (250 mL) and dried over sodium sulphate andfiltered. The filtrate solvents were removed in vacuo to afford a yellowsolid which was purified by flash chromatography on silica gel (100 g),eluting with a 1:19 mix of 7N ammonia in methanolsolution:dichloromethane. This affords the title compound (2.0 g, 42%)as a colourless solid.

LCMS: (Method A) RT=1.04 min; m/z=397 [M+H]⁺.

Step 2 3-[5-(3-Hydroxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylicacid pyridin-3-ylamide

This compound was prepared by the method outlined for example 5 step 6.Thus 3-(5-iodo-pyridin-2-yloxy)azetidine-1-carboxylic acidpyridin-3-ylamide (300 mg, 0.76 mmol) was reacted with3-hydroxyphenylboronic acid (156 mg, 1.14 mmol) to afford a crudeproduct purified by flash chromatography on silica gel eluting withsolvent gradient of 1:19 to 1:9 7N ammonia in methanolsolution:dichloromethane. This affords the title compound (130 mg, 47%)as a colourless powder.

LCMS: (Method A) RT=0.97 min; m/z=363 [M+H]⁺.

Step 33-{5-[3-(2-Methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridin-3-ylamide

Potassium carbonate (23 mg, 165 μmol) was added to a solution of3-[5-(3-hydroxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acidpyridin-3-ylamlde (20 mg 55 μmol), in DMF (0.5 mL). 2-Bromoethyl methylether (6 μL, 66 μmol) was added and the reaction mixture was heated to100° C. in microwave synthesiser for 1 hr. The reaction mixture wasallowed to cool and solvent removed in vacuo. The crude product waspurified by preparative HPLC to afford the title product as a colourlesssolid (6.7 mg, 29%).

LCMS: (Method A) RT=1.11 min; m/z=421 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.32 (s, 3H), 3.68 (m, 2H), 3.99 (m, 2H),4.17 (m, 2H), 4.44 (m, 2H), 5.39 (m, 1H), 6.92-6.97 (m, 1H), 7.00 (d,1H, J=8.6 Hz), 7.21-7.25 (m, 2H), 7.27 (dd, 1H, J=8.3, 4.8 Hz), 7.37(dd, 1H, J=8.1, 8.1 Hz), 7.93 (dm, 1H). 8.09 (dd, 1H, J=8.6, 2.6 Hz),8.15 (dd, 1H, J=4.5, 1.6 Hz), 8.49 (d, 1H, J=2.1 Hz), 8.66 (d, 1H, J=2.1Hz), 8.75 (s, 1H).

Example 93-{5-[3-(2-Benzyloxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

Step 12-[3-(2-Benzyloxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

This compound was prepared by the method outlined for example 5 step 5.Thus 3-hydroxyphenylboronic acid pinacol ester (500 mg, 2.27 mmol) wasreacted with benzyl-2-bromoethyl ether (0.54 mL, 3.41 mol) and the crudeproduct after work up used without further purification.

Step 23-{5-[3-(2-Benzyloxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidin-1-carboxylicacid pyridazin-3-ylamide

This compound was prepared by the method outlined for example 5 step 6.Thus 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide (example 7, step 1) (600 mg, 1.15 mmol) was reactedwith2-[3-(2-benzyloxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(1.5 equiv). Crude product purified by flash chromatography on silicagel eluting with 4:1 ethyl acetate:hexane to afford title compound (214mg, 28%) as a brown foam.

LCMS: (Method B) RT=1.37 min; m/z=498 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.80 (m, 2H), 4.04 (m, 2H), 4.23 (m, 2H),4.49 (m, 2H), 4.57 (s, 2H), 5.40 (m, 1H), 6.96 (m, 1H), 6.99 (d, 1H,J=8.6 Hz), 7.21-7.25 (m, 2H), 7.29 (m, 1H), 7.33-7.39 (m, 5H), 7.59 (dd,1H, J=9.1, 4.8 Hz), 8.08 (dd, 1H, J=8.6, 2.5 Hz), 8.15 (dd, 1H, J=9.1,1.3 Hz), 8.49 (d, 1H, J=2.5 Hz), 8.84 (dd, 1H, J=4.5, 1.3 Hz), 9.97(brs, 1H).

Example 103-{5-[3-(2-Hydroxy-ethoxy)-phenyl]-pyridine-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

Step 13-{5-[3-(2-Hydroxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

3-{5-[3-(2-Benzyloxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide (Example 9, 325 mg, 0.65 mmol) was dissolved inanhydrous dichloromethane (10 mL) under a nitrogen atmosphere. Themixture was cooled with an ice water bath and boron tribromide indichloromethane solution (1M, 0.98 mL, 0.98 mmol) was added drop-wiseaffording a precipitate. The reaction mixture was stirred at 0° C. for 2hr. The precipitate was collected by filtration and purified by flashchromatography on silica gel eluting with ethyl acetate, then 5-10%methanol in DCM. Further purification by preparative HPLC at pH4afforded title compound (13 mg, 5%) as colourless solid.

LCMS: (Method B) RT=1.05 min; m/z=408 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.73 (m, 2H), 4.00-4.09 (m, 4H), 4.49 (m,2H), 4.89 (t, 1H, J=5.5 Hz), 5.40 (m, 1H), 6.94 (dm, 1H), 7.00 (d, 1H,J=8.6 Hz), 7.20-7.25 (m, 2H), 7.37 (dd, 1H, J=8.1, 8.1 Hz), 7.58 (dd,1H, J=9.1, 4.8 Hz), 8.08 (dd, 1H, J=8.6, 2.8 Hz), 8.15 (dd, 1H, J=8.8,1.2 Hz), 8.49 (d, 1H, J=1.7 Hz), 8.84 (dd, 1H, J=4.8, 1.7 Hz), 9.97(brs, 1H).

Example 113-{5-[2-Methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

Step 1 Acetic acid 4-methoxy-phenyl ester

Triethylamine (14.55 mL, 104.43 mmol) was added to an ice-bath cooledsolution of 4-methoxyphenol (5.185 g, 41.77 mmol) in anhydrous ether(200 mL) under nitrogen atmosphere. Acetyl chloride (5.94 mL, 83.53mmol) was added drop-wise and reaction mixture then allowed to warm toroom temperature and stir for a further 10 min. The reaction mixture waspartitioned between ethyl acetate and sat aqueous sodium bicarbonatesolution. The phases were separated and the organic phase was dried oversodium sulphate, filtered and filtrate solvents removed in vacuo toafford the title compound (7.45 g, quant) as a brown liquid.

LCMS: (Method A) RT=1.88 min; no ionisation.

TLC: R_(f)=0.72 (7:3 EtOAc:Hexane)

Step 2 Acetic acid 3 oxy-phenyl ester

Acetic acid (2.24 mL, 7.4 mmol) was added to a mixture of acetic acid4-methoxy-phenyl ester (1.0 g, 6.02 mmol) and sodium acetate (940 mg.11.46 mmol). A solution of bromine (0.37 mL, 6.02 mmol) in acetic acid(2.1 mL) was added drop-wise and mixture stirred for 18 hr at ambienttemperature. A further 0.6 mL of acetic add was added followed by afurther 0.1 mL of bromine. Mixture was stirred for 2 hours, thenpartitioned between ethyl acetate (100 mL) and water (100 mL). Thephases were separated and organic layer was washed sequentially withsat. aqueous sodium bicarbonate solution (2×150 mL), sat. aqueous sodiumthiosulphate solution (100 mL) and sat. aqueous sodium chloride solution(100 mL). Organic phase was dried over sodium sulphate, filtered andfiltrate solvents removed in vacuo to afford a oil which was purified byflash chromatography on silica gel, eluting with a gradient of 0-10%ethyl acetate in hexane to afford title compound (1.2 g, 81%) as alight-brown oil.

LCMS: (Method A) RT=2.11 min; no ionisation.

TLC: R_(f)=0.20 (1:9 EtOAc:Hexane)

Step 3 3-Bromo-4-methoxy-phenol

A solution of potassium hydroxide (290 mg, 5.19 mmol) In water (2.5 mL)was added to a solution of acetic acid 3-bromo-4-methoxy-phenyl ester(1.2 g, 4.9 mmol) in methanol (18.5 mL). Mixture was stirred at ambienttemperature for 30 min, then solvents were removed in vacuo and water(40 mL) added. The mixture was made acidic by drop-wise addition of 1.2M aq HCl solution (4.3 mL) and the mixture extracted withdichloromethane (2×40 mL). Combined organics were dried over sodiumsulphate, filtered and filtrate solvents evaporated in vacuo to give thetitle compound (976 mg, 98%) as a pale yellow solid.

LCMS: (Method A) RT=2.11 min; no ionisation

TLC: R_(f)=0.28 (1:4 EtOAc:Hexane)

Step 4 2-Bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzene

2-bromoethyl methyl ether (0.07 mL, 0.74 mmol) was added to a mixture ofpotassium carbonate (136 mg, 0.99 mmol) and 3-bromo-4-methoxy-phenol(100 mg, 0.49 mmol) In DMF (2 mL) and mix heated at 100° C. for 1 hr.Reaction mixture was allowed to cool and partitioned between ethylacetate (20 mL×2) and water (20 mL). The combined organic phases werewashed with sat. aqueous sodium chloride solution (40 mL) and dried oversodium sulphate. Solvents were removed in vacuo to afford a crude oilwhich was purified by flash chromatography on silica gel, eluting with agradient of 0-10% ethyl acetate in hexane to afford the title compound(113 mg, 88%) as a colourless liquid.

LCMS: (Method A) RT=2.12 min; no ionisation.

TLC: R_(f)=0.34 (1:4 EtOAc:Hexane)

Step 53-{5-[2-Methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylicacid pyridazin-3-ylamide

A solution of 2-bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzene (110 mg,0.42 mmol) in anhydrous THF (2 mL) was cooled to −78° C. with a CO₂—acetone bath under a nitrogen atmosphere. Triisopropyl borate (0.19 mL,0.842 mmol) was added, followed by n-butyl lithium solution (2.5M inhexanes, 0.22 mL, 0.55 mmol). The mixture was allowed to warm to ambienttemperature the solvents were removed in vacuo to afford a colourlesssolid. To the crude boronic acid was added3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide (Example 7, step 1) (150 mg, 0.38 mmol), 1N aqueoussodium bicarbonate solution (1.26 mL), DMF (7 mL) and1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (15 mg). Nitrogen gas bubbled through mix for 5 minutes andreaction mixture heated at 80° C. for 2 hr. Mix was allowed to cool,partitioned between ethyl acetate (30 mL) and water (30 mL). Organicphase was separated then washed with sat. aqueous sodium chloridesolution (60 mL) and dried over sodium sulphate. Solvents were removedin vacuo to afford a crude oil which was purified by flashchromatography on silica gel, eluting with a gradient of 0-10% ethylacetate in hexane to afford the title compound (77 mg, 41%) as a paleyellow foam.

LCMS: (Method A) RT=1.94 min; m/z=450 [M−H]⁻ (negative ionisation).

TLC: R_(f)=0.21 (100% EtOAc)

¹H NMR: (400 MHz, CDCl₃) δ 3.45 (s, 3H), 3.75 (m, 2H), 3.77 (s, 3H),4.12 (m, 2H), 4.21 (m, 2H), 4.56 (m, 2H), 5.48 (m, 1H), 6.83 (d, 1H,J=8.6 Hz), 6.91 (m, 3H), 7.42 (dd, 1H, J=9.1, 4.8 Hz), 7.47 (brs, 1H),7.82 (dd, 1H, J=8.6, 2.5 Hz), 8.25 (d, 1H, J=2.3 Hz) 8.38 (dd, 1H,J=9.1, 1.3 Hz), 8.84 (dd, 1H, J=4.5, 1.3 Hz).

Example 123-[5-(2,5-Dimethoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acidpyridazin-3-ylamide

This compound was prepared by the method outlined for example 5 step 6.Thus 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrazin-2-ylamide (100 mg, 0.25 mmol) was reacted with2,5-Dimethoxybenzeneboronic acid (Cas. No 107099-99-0, 69 mg, 0.38 mmol)to afford title compound (84 mg, 83%) as an off-white powder.

LCMS: (Method B) RT=1.19 min; m/z=408 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.72 (s, 3H), 3.75 (s, 3H), 4.00-4.08 (m,2H), 4.46-4.51 (m, 2H), 5.36-5.41 (m, 1H), 6.91-6.97 (m, 3H), 7.04-7.06(m, 1H), 7.58 (dd, 1H, J=4.5, 9.1 Hz) 7.89 (dd, 1H, J=2.3, 8.6 Hz), 8.15(dd, 1H, J=1.5, 9.1 Hz), 8.27 (d, 1H, J=1.7 Hz), 8.85 (dd, 1H, J=1.4,4.6 Hz), 9.96 (s, 1H).

Example 13 3-(5-Phenyl-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide

This compound was prepared by the method outlined for example 5 step 6.Thus 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrazin-2-ylamide (750 mg, 1.89 mmol), benzeneboronic acid (345 mg, 2.83mmol) potassium carbonate (783 mg, 5.67 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complexwith dichloromethane; 155 mg, 0.19 mmol) and THF-HO (10:1; 0.15 mL) weremixed, sealed in two microwave vials and heated at 100° C. for 2 hours.The vials were combined, evaporated and loaded onto a 50 g SiO₂cartridge in DCM, and dried thoroughly. The product was eluted with 1:1iso-hexane:EtOAc to EtOAc and the product obtained after evaporation ofthe product-containing fractions triturated in 2:1 diethylether-iso-hexane and collected by filtration to give the product (702mg, 54%) as a white powder.; mp 201-202° C.; R_(f) 0.17 (EtOAc); LCMS rt1.19 mins [Method B], m/z 348 ([M+H]J, 100%); □_(H)(399 MHz; DMSO-d₆)9.97 (1H, br s), 8.85 (1H, dd, J=4.5 and 1.3 Hz), 8.48 (1H, dd, J=2.5and 0.5 Hz), 8.15 (1H, dd, J=9.1 and 1.5 Hz), 8.08 (1H, dd, J=8.6, 2.5Hz), 7.68-7.66 (2H, m), 7.59 (1H, dd, J=9.1 and 4.5 Hz), 7.49-7.45 (2H,m), 7.39-7.36 (1H, m), 7.01 (1H, dd, J=8.6 and 0.5 Hz), 5.40 (1H, tt,J=6.6 and 4.0 Hz), 4.48 (2H, dd, J=8.6 and 6.6 Hz) and 4.04 (2H, dd,J=9.6 and 3.0 Hz).

Example 143-[5-(2,6-Difluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acidpyridazin-3-ylamide

3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrimidin-4-ylamide (50 mg, 0.126 mmol), potassium2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), triethylamine(0.05 ml, 0.38 mmol)1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (5 mg, 5 mole %) and EtOH (108 mg, 0.786 mmol) were combinedand heated at 80° C. for 16 h. The reaction had not gone to completionso further potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132mmol), 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II)complex with CH₂Cl₂ (5 mg, 5 mole %) and triethylamine (0.05 ml, 0.38mmol) were added and the mixture heated for a further 5 h. The reactionmixture was allowed to cool before being passed through a pad of celiteand washed through with EtOAc and MeOH. These organics were evaporatedin vacuo, to afford a crude oil, which was purified by flashchromatography, eluting with a gradient of 0 to 4% MeOH in CH₂Cl₂ to aafford still impure product as a brown oil. This was purified by HPLC(pH 4. HCO₂NH₄/HCO₂H/H₂O/MeCN) to afford the desired product as a whitesolid (8 mg, 17%)

LCMS: (Method B) RT=1.2 min; m/z=384 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ 4.06 (m, 2H), 4.50 (m, 2H), 5.41 (m, 1H),7.07 (dd, 1H, J=8.6, 0.5 Hz), 7.26 (m, 2H), 7.51 (m, 1H), 7.59 (dd, 1H,J=4.5 Hz), 7.89 (m, 1H), 8.15 (dd, 1H, J=9.0, 1.5 Hz) 8.28 (m, 1H), 8.85(dd, 1H, J=4.5, 1.3 Hz), 9.97 (bs, 1H).

Example 151-(3-{5-[2-Chloro-5-(2-methoxy-ethoxy)-phenyl]pyridin-2-yloxy}-azetidin-1-yl)-2-pyridazin-3-yl-ethanone

Step 1 4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol

2-chloro-5-hydroxyphenyl boronic acid (409 mg, 2.37 mmol), pinacol (336mg, 2.85 mmol), toluene (20 ml) and 4 angstrom molecular sieves (400 mg)were combined and heated at 120° C. for 2 h. The reaction mixture wasallowed to cool and was then partitioned between EtOAc (2×30 ml) andwater (30 ml). The combined organics were washed with brine (20 ml),dried (Na₂SO₄) and evaporated in vacuo to afford the desired product asa white solid (500 mg, 83%).

LCMS: (Method A) RT=2.35 min; m/z=253 [M−H]⁻.

Step 21-(3-{5-[2-Chloro-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidin-1-yl)-2-pyridazin-3-yl-ethanone

4-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (495mg, 1.95 mmol), PPh₃ (765 mg, 2.92 mmol) and THF (11 ml) were combinedunder N₂ at RT. 2-methoxyethanol (0.18 ml, 2.34 mmol) was then added andthe reaction mixture stirred for 5 min. The mixture was then cooled to0° C. and DIAD (0.57 ml, 2.92 mmol) added dropwise. The mixture was thenallowed to warm to RT and stirred for a further 2 h. The reactionmixture was partitioned between EtOAc (2×30 ml) and water (30 ml). Thecombined organics were washed with brine (30 ml), dried (Na₂SO₄) andevaporated in vacuo to afford the crude product as a yellow oil, whichwas purified by flash chromatography, eluting with a gradient of 0 to50% EtOAc in Hexane to a afford still impure product as an off-whitesolid (316 mg, impure). This was combined with3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrimidin-4-ylamide (64 mg, 0.162 mmol), 1M NaHCO₃ solution (0.19 ml,0.194 mmol), PdCl₂(PPh₃)₂ (6 mg, 2 mol %) and DMF (4 ml). The mixturewas degassed by bubbling N₂ through it for 5 min. and was subsequentlyheated at 80° C. for 2 h under N₂. The reaction was allowed to coolbefore being filtered through a pad of celite before being partitionedbetween EtOAc (2×20 ml) and water (25 ml). The combined organics weredried (Na₂SO₄) and evaporated in vacuo to give a crude oil, which waspurified by flash chromatography, eluting with a gradient of 0 to 10%MeOH in CH₂Cl₂ to a afford still impure product as a brown oil. This waspurified by HPLC (pH 4, HCO₂NH₄/HCO₂H/H₂/MeCN) to afford the desiredproduct as a white solid (48 mg, 26%) LCMS: (Method B) RT=1.28 min;m/z=456 [M+H]⁺

¹H NMR: (400 MHz, CDCl₃) δ 3.30 (s, 3H), 3.65 (m, 2H), 4.05 (m, 2H),4.15 (m, 2H), 4.50 (m, 2H), 5.41 (m, 1H), 7.01 (m, 3H), 7.47 (d, 1H,J=8.8 Hz), 7.59 (dd, 1H, J=4.5 Hz), 7.89 (dd, 1H, J=8.6, 2.5 Hz), 8.15(dd, 1H, J=9.1, 1.5 Hz) 8.25 (d, 1H, J=2.5 Hz), 8.85 (dd, 1H, J=4.5, 1.5Hz), 9.97 (bs, 1H).

Example 163-[5-(2-Fluoro-phenyl]-pyridin-2-yloxy]-azetidine-1-carboxylic acidpyrazin-2-ylamide

To a mixture of 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyrazin-2-ylamide (Example 6 step 4; 100 mg, 0.285 mmol),2-fluorophenylboronic acid (Aldrich, 60 mg, 0.428 mmol), potassiumcarbonate (118 mg, 0.86 mmol) and1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (23 mg, 10 mole %) in a microwave vial was added THF/H₂O(10:1, 3 mL). Nitrogen gas was bubbled through the mixture for 5 minsand the vial sealed and heated at 100° C. in microwave synthesizer for20 min. The cooled reaction mixture was diluted with ethyl acetate (20mL) and filtered through celite (2.5 g IST cartridge). A further 10 mLof ethyl acetate was washed through the celite pad and combined filtratewas washed sequentially with water (25 mL) then sat. sodium chloridesolution (25 mL). Mixture was dried over sodium sulphate and filtered.Filtrate solvents were removed in vacuo to afford a crude product, whichwas purified by flash chromatography, eluting with a gradient of 50 to100% ethyl acetate in hexane to a afford a gummy solid. which wastriturated with diethyl ether, filtered and dried to afford the titlecompound as colourless solid (67 mg, 64%) LCMS: (Method A) RT=2.09 min;m/z=366.1 [M+H]⁺.

TLC: R_(f)=0.16 (EtOAc/Hexane, 1:1)

¹H NMR: (400 MHz, DMSO-d₆) δ 4.00-4.07 (m, 2H), 4.44-4.57 (m, 2H),5.37-5.43 (m, 1H), 7.03 (d, 1H, J=8.6 Hz), 7.29-7.37 (m, 2H), 7.40-7.48(m, 1H), 7.54-7.60 (m, 1H), 7.95-7.99 (m, 1H), 8.22 (d, 1H, J=2.5 Hz),8.29-8.31 (m, 1H), 8.34-8.36 (brm, 1H), 9.17 (d, 1H, J=1.6 Hz), 9.65 (s,1H).

Example 173-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acidpyridazin-3-ylamine

A solution of 2-methoxyphenyl boronic acid in THF/H₂O (10:1; 40 mL) wasadded to a microwave vial containing3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide (prepared as in Example 19 Step 1) 1.5 g, 4.28 mmol)and potassium carbonate (1.78 g, 12.86 mmol). Nitrogen gas was bubbledthrough the mixture for 5 mins then1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (0.350 g, 10 mole %) was added and the vial sealed andheated at 100° C. in microwave synthesiser for 30 min. The cooledreaction mixture was diluted with ethyl acetate (100 mL) and washedsequentially with sat. aqueous sodium carbonate solution (100 mL) thensat. sodium chloride solution (100 mL). Mixture dried over magnesiumsulphate and filtered. Filtrate solvents were removed in vacuo to afforda brown gum, which was purified by flash chromatography, eluting with agradient of 80 to 100% ethyl acetate in hexane to a afford a pale yellowsolid. Product was triturated with diethyl ether, filtered and dried toafford the title compound as a white solid (1.098 g, 68%)

LCMS: (Method A) RT=2.04 min; m/z=378 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.78 (s, 3H), 4.04 (brm, 2H), 4.49 (brm,2H), 5.39 (m, 1H), 6.96 (d, 1H, J=8.6 Hz), 7.04 (m, 1H), 7.13 (d, 1H,J=8.2 Hz), 7.33 (dd, 1H, J=7.5, 1.6 Hz), 7.37 (m, 1H), 7.59 (dd, 1H,J=9.1, 4.7 Hz), 7.88 (dd, 1H, J=8.6, 2.5 Hz), 8.16 (dd, 1H, J=9.1, 1.4Hz), 8.25 (d, 1H, J=2.5 Hz), 8.85 (dd, 1H, J=4.7, 1.4 Hz), 9.96 (s, 1H).

Example 18 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidin-1-carboxylicacid pyridazin-3-ylamide

A solution of 4-fluorophenyl boronic acid (0.254 mg, 1.81 mmol) inTHF/H₂O (10:1; 10 mL) was added to a microwave vial containing3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide (Example 7, Step 1) (0.480 g, 1.21 mmol) andpotassium carbonate (0.50 g, 3.63 mmol). Nitrogen gas was bubbledthrough the mixture for 5 mins then1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (0.099 g, 10 mole %) was added and the vial sealed andheated at 100° C. in microwave synthesiser for 30 min. The cooledreaction mixture was diluted with ethyl acetate (20 mL) and washedsequentially with saturated aqueous sodium carbonate solution (20 mL)then saturated sodium chloride solution (20 mL). The mixture was driedover magnesium sulphate and filtered. Filtrate solvents were removed invacuo to afford a brown gum, which was purified by flash chromatography,eluting with a gradient of 50% to 100% ethyl acetate in hexane to aafford a white solid (0.235 g, 53%) LCMS: (Method B) RT=1.20 min;m/z=366 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 4.05 (brm, 2H), 4.50 (brm, 2H), 5.41 (m,1H), 7.04 (d, 1H, J=8.6 Hz), 7.29-7.38 (m, 2H), 7.45 (m, 1H), 7.54-7.62(m, 2H), 7.97 (m, 1H), 8.15 (dd, 1H, J=9.1, 1.4 Hz), 8.36 (app s, 1H),8.85 (dd, 1H, J=4.6, 1.4 Hz), 9.97 (s, 1H).

Example 193-[5-(2-Fluoro-3-methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylicacid pyridazin-3-ylamide

Step 1 Synthesis of 3-(5-Bromo-pyridin-2-yloxy)-azetidine-1-carboxylicacid pyridazin-3-ylamide

To an ice-bath cooled solution of sodium hydride (60 wt % in mineraloil, (0.946 g, 23.6 mmol) in DMF (21 mL) under nitrogen atmosphere wasadded (dropwise) a solution of 3-aminopyridazine (1.24 g, 13.01 mmol) inDMF (21 mL). After several minute a solution of3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenylester (Example 10, step 3; 4.66 g, 11.83 mmol) in DMF (17 mL) was added.After 5 min the cooling bath was removed and reaction allowed to warm toambient temperature and stir for 1.5 hr. Saturated sodium bicarbonatesolution (500 mL) was added and the mixture was extracted with EtOAc(4×400 mL). Combined organic phases were washed with sat sodium chloridesolution (500 mL), dried over sodium sulphate and filtered. The filtratesolvents were removed in vacuo to afford a crude product that wastriturated with diethyl ether to afford the title compound (3.32 g, 80%)as a colourless solid.

LCMS: (Method A) RT=1.81 min; m/z=352 [M+H]⁺.

Step 23-[5-(2-Fluoro-3-methoxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylicacid pyridazin-3-ylamide

A solution of 2-fluoro-3-methoxyphenyl boronic acid (0.065 g, 0.38 mmol)in THF/H₂O (10:1; 2 mL) was added to a microwave vial containing3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acidpyridazin-3-ylamide (prepared in Step 1) (0.100 g, 0.25 mmol) andpotassium carbonate (0.105 g, 0.76 mmol). Nitrogen gas was bubbledthrough the mixture for 5 mins then1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (0.020 g, 10 mole %) was added and the vial sealed andheated at 100° C. in microwave synthesiser for 30 min. The cooledreaction mixture was diluted with ethyl acetate (20 mL) and washedsequentially with sat. aqueous sodium carbonate solution (20 mL) thensat. sodium chloride solution (20 mL). Mixture dried over magnesiumsulphate and filtered. Filtrate solvents were removed in vacuo to afforda brown gum, which was purified by flash chromatography, eluting with agradient of 80 to 100% ethyl acetate in hexane to a afford an off-whitesolid (0.079 g, 78%).

LCMS: (Method B) RT=1.18 min; m/z=408 [M+H]⁺.

¹H NMR: (400 MHz, DMSO-d₆) δ 3.88 (s, 3H), 4.05 (brm, 2H), 4.49 (brm,2H), 5.41 (m, 1H), 7.03 (d, 1H, J=8.6 Hz), 7.08 (m, 1H), 7.17-7.26 (m,2H), 7.59 (dd, 1H, J=9.1, 4.6 Hz), 7.94 (m, 1H), 8.15 (dd, 1H, J=9.1,1.4 Hz), 8.33 (app s, 1H), 8.85 (dd, 1H, J=4.6, 1.4 Hz), 9.96 (s, 1H).

Example 203-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(6-methyl-pyridazin-3-yl)-amide

Step 1 2-(1-Benzhydryl-azetidin-3-yloxy)-5-(2-fluoro-phenyl)-pyridine

To a solution of 2-fluoro-boronic acid (1.45 g, 10.36 mmol) and2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (3.53 g, 7.97 mmol) inDMF (180 mL) was added sodium hydrogen carbonate (2.01 g) suspended inwater (20 mL). The reaction mixture was stirred under a flow of nitrogenfor 1 hr. then1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complexwith CH₂Cl₂ (326 mg, 5 mole %) was added and stirred for 18 hrs at roomtemperature.

The reaction mixture was concentrated in vacuo, diluted with ethylacetate (400 mL) filtered over Celite and washed sequentially with sat.aqueous sodium hydrogen carbonate solution (3×150 mL) then sat. sodiumchloride solution (150 mL). Mixture dried over magnesium sulphate andfiltered. Filtrate solvents were removed in vacuo and the residue waspurified by flash chromatography (4% Methanol in DCM) to give the titlecompound (2.18 g, 67%)

LCMS: (Method A) RT=2.54 min; m/z=411 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ 3.12-3.20 (m, 2H), 3.74-3.80 (m, 2H), 4.45(s, 1H), 5.27-5.33 (m, 1H), 6.81 (d, 1H, J 8.6), 7.11-7.22 (m, 4H),7.28-7.40 (m, 6H), 7.43-7.46 (m, 4H), 7.75-7.78 (m, 1H), 8.21-8.28 (m,1H).

Step 2 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylicacid 4-nitro-phenyl ester

4-nitrophenyl chloroformate (734 mg g, 3.64 mmol) was added to a stirredsolution of2-(1-Benzhydryl-azetidin-3-yloxy)-5-(2-fluoro-phenyl)-pyridine (996 mg,2.43 mol) in dichloromethane (25 mL) at ambient temperature. Theresulting solution was stirred at ambient temperature for 18 hr, dilutedwith dichloromethane (150 mL) and washed sequentially with sat. aqueoussodium hydrogen carbonate solution (3×150 mL) then sat. sodium chloridesolution (150 mL). The organic phase was dried over magnesium sulphateand filtered. Filtrate solvents were removed in vacuo and the residuewas purified by trituration with Methyl tertiary butyl ether (25 mL) togive after filtration a yellow solid (786 mg, 79%).

LCMS: (Method A) RT=2.46 min; m/z=410 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ 4.20-4.26 (m, 1H), 4.26-4.34 (m, 1H),4.52-4.60 (m, 1H), 4.60-4.72 (m, 1H), 5.46-5.52 (m, 1H), 6.90 (d, 1H, J8.6), 7.15-7.25 (m, 2H), 7.33 (d, 2H, J 9.4), 7.31-7.43 (m, 3H),7.82-7.86 (m, 1H), 8.25 (d, 2H, J 9.1), 8.28-8.32 (m, 1H).

Step 3 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylicacid (6-methyl-pyridazin-3-yl)-amide

To a solution of 6-Methyl-pyridazin-3-ylamine (60 mg, 0.55 mmol, [Cas.No 18591-82-7]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg,0.5 mmol, 60% disp. In mineral oil). After stirring at 0° C. for 15 min.a solution of3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid4-nitro-phenyl ester (102 mg, 0.25 mmol) In DMF (4 mL) was addeddropwise. After stirring for 16 hrs at ambient temperature the reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL)and washed sequentially with sat. aqueous sodium hydrogen carbonatesolution (2×50 mL) then sat sodium chloride solution (50 mL). Mixturedried over magnesium sulphate and filtered. Filtrate solvents wereremoved in vacuo and the residue was purified by flash chromatography(40%, ethyl acetate in DCM) to give the title compound (48 mg, 49%)LCMS: (Method A) RT=1.86 min; m/z=380 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ 2.60 (s, 3H), 4.19-4.23 (m, 2H), 4.54-4.58(m, 2H), 5.45-5.50 (m, 1H), 6.88 (d, 1H, J 8.6), 7.14-7.24 (m, 2H),7.27-7.41 (m, 3H), 7.80-7.84 (m, 1H), 8.25-8.30 (m, 2H).

Example 213-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(6-methoxy-pyridazin-3-yl)-amide

To a solution of 6-Methoxy-pyridazin-3-ylamine (39 mg, 0.31 mmol, [Cas.No. 7252-84-8]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg,0.5 mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min.a solution of3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was addeddropwise. After stirring for 16 hrs at ambient temperature the reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL)and washed sequentially with sat. aqueous sodium hydrogen carbonatesolution (2×50 mL) then sat sodium chloride solution (50 mL). Mixturedried over magnesium sulphate and filtered. Filtrate solvents wereremoved in vacuo and the residue was purified by flash chromatography(ethyl acetate) to give the title compound (35 mg, 37%)

LCMS: (Method A) RT=1.97 min; n/z=396 [M+H]⁺.

¹H NMR: (400 MHz, CDCl₃) δ 4.03 (s, 3H), 4.21-4.25 (m, 2H), 4.55-4.59(m, 2H), 5.45-5.50 (m, 1H), 6.88 (d, 1H, J 8.6), 7.02 (d, 1H, J 9.6),7.15-7.25 (m, 2H), 7.31-7.42 (m, 2H), 7.81-7.84 (m, 1H), 8.28 (bs, 1H),8.35 (d, 1H, J 9.3).

Example 223-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(5-methyl-[1,3,4]oxadiazol-2-yl)-amide

To a solution of 5-Methyl-[1,3,4]oxadiazol-2-ylamine (31 mg, 0.31 mmol,[Cas. No. 52838-39-8]) in DMF (3 mL) at 0° C. was added sodium hydride(20 mg, 0.5 mmol. 60% disp. In mineral oil). After stirring at 0° C. for15 min. a solution of3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic add4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was addeddropwise. After stirring for 16 hrs at ambient temperature the reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL)and washed sequentially with sat. aqueous sodium hydrogen carbonatesolution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixturedried over magnesium sulphate and filtered. Filtrate solvents wereremoved in vacuo and the residue was purified by preparative HPLC togive the title compound (10 mg, 11%)

LCMS: (Method A) RT=1.77 min; m/z=370 [M+H]⁺.

¹H NMR: (400 MHz, CD₃OD) δ 2.34 (s, 3H), 3.96-4.00 (m, 2H), 4.36-4.40(m, 2H), 5.33-5.39 (m, 1H), 6.94 (d, 1H, J 8.8), 7.18-7.29 (m, 2H),7.36-7.41 (m, 1H), 7.46-7.50 (m, 1H), 7.88-7.91 (m, 1H), 8.29 (bs, 1H).

Example 23 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]azetidine-1-carboxylicacid pyridazin-4-ylamide

To a solution of Pyridazin-4-ylamine (30 mg, 0.31 mmol, [Cas. No.20744-39-2]) in DMF (3 mL) at 0° C. was added sodium hydride (20 mg, 0.5mmol, 60% disp. in mineral oil). After stirring at 0° C. for 15 min. asolution of3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was addeddropwise. After stirring for 16 hrs at ambient temperature the reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL)and washed sequentially with sat. aqueous sodium hydrogen carbonatesolution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixturedried over magnesium sulphate and filtered. Filtrate solvents wereremoved in vacuo and the residue was purified by preparative HPLC togive the title compound (15 mg, 16%)

LCMS: (Method A) RT=1.74 min; m/z=366 [M+H]⁺.

¹H NMR (400 MHz. CD₃OD) δ 4.15-4.18 (m, 2H), 4.56-4.61 (m, 2H),5.46-5.51 (m, 1H), 6.98 (d, 1H, J 8.6), 7.19-7.29 (m, 2H), 7.37-7.42 (m,1H), 7.46-7.50 (m, 1H), 7.91-7.94 (m, 1H), 7.95-7.98 (m, 1H), 8.31 (bs,1H), 8.87 (d, 1H, J 6.1), 9.26-9.28 (m, 1H).

Example 24 6-Chloro-4-methyl-pyridazin-3-ylamine and6-Chloro-5-methyl-pyridazin-3-ylamine

A solution of 3,6-Dichloro-4-methyl-pyridazine (3.0 g, 18.40 mmol) inAmmonia (28-30%; 150 mL) was heated at 130° C. in a pressurised reactionvessel for 16 hrs. The reaction mixture was cooled to ambienttemperature and extracted with dichloromethane (10×100 mL) The organiclayers were combined, dried (MgSO₄), filtered and concentrated to give amixture of the titled compounds (853 mg; 32%).

LCMS: (Method A) RT=0.45 min; m/z=144 [M+H].

¹H NMR: (400 MHz, DMSO-d₆) δ 2.07 (s, 3H), 2.18 (s, 3H), 6.47 (bs, 2H),6.49 (bs, 2H), 6.74 (s, 1H), 7.31 (s, 1H).

Example 25 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidin-1-carboxylicacid (5-methyl-pyridazin-3-yl)-amide and3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(4-methyl-pyridazin-3-yl)-amide

To a solution of the mixture 6-Chloro-4-methyl-pyridazin-3-ylamine and6-Chloro-5-methyl-pyridazin-3-ylamine (143 mg, 1.0 mmol) In DMF (6 mL)at 0° C. was added sodium hydride (80 mg, 2.0 mmol, 60% disp. in mineraloil). After stirring at 0° C. for 15 min. a solution of3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid4-nitro-phenyl ester (204 mg, 0.5 mmol) in DMF (6 mL) was addeddropwise. After stirring for 16 hrs at ambient temperature the reactionmixture was concentrated in vacuo, diluted with ethyl acetate (50 mL)and washed sequentially with sat. aqueous sodium hydrogen carbonatesolution (2×50 mL) then sat. sodium chloride solution (50 mL). Mixturedried over magnesium sulphate and filtered. Filtrate solvents wereremoved in vacuo and the regioisomers were partially separated by flashchromatography (4% Methanol in DCM) which were separately hydrogenatedat atmospheric pressure (10% Pd/C, Ethanol) to give after preparativeHPLC purification the regioisomers.

3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(5-methyl-pyridazin-3-yl)-amide (24 mg, 6%).

LCMS: (Method A) RT=1.91 min; m/z=380 [M+H].

¹H NMR: (400 MHz, CD₃OD) δ 2.38 (s, 3H), 4.15-4.18 (m, 2H), 4.56-4.61(m, 2H), 5.45-5.51 (m, 1H), 6.98 (d, 1H, J 8.6), 7.19-7.29 (m, 2H),7.37-7.41 (m, 1H), 7.46-7.50 (m, 1H), 7.90-7.93 (m, 1H), 8.12 (bs, 1H),8.31 (bs, 1H), 8.69 (bs, 1H).3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid(4methyl-pyridazin-3-yl)-amide (11 mg, 3%)

LCMS: (Method A) RT=1.82 min; m/z=380 [M+H]⁺.

Biological Results Part A Rat FAAH Inhibition Assay

Active rat FAAH protein (30-579) was isolated as described in theliterature. The coding sequence of amino adds 30-579 of rat FAAH werecloned into the expression vector pET28a to provide an N-terminalHis-tag. Following expression, the His-tagged FAAH (30-579) was isolatedusing a method based on Patricelli at al., 1998; Biochemistry vol 37, p15177 with a combination of chelating sepharose, heparin sepharose andsize exclusion chromatography.

FAAH activity was determined by measuring the liberation of the highlyfluorescent 7-amino, 4-methyl Coumarin (AMC) generated during hydrolysisof the substrate Arachidonoyl 7-Amino, 4-methyl Coumarin Amide (AAMCA)by FAAH. Inhibition of FAAH activity was determined as a percentagereduction of the fluorescence determined in the absence of compound.

The assay was carried out in black-walled, clear bottom, 384-wellplates. 27.5 μl of FAAH protein (in FAAH assay buffer: 50 mM Hepes,0.01% Triton X-100, 1 mM EDTA, 0.5 mg/ml BSA (fatty-acid-free), pH 8.2)was pre-incubated, at 120 nM, with increasing concentrations ofcompounds (2.5 μl in 100% DMSO) for 0, 1 or 3 hours at room temperature.2.5 μl of DMSO was added for ‘total’ controls (100% FAAH activity) and2.5 μl of URB-597, a known inhibitor of FAAH activity, (at a final,saturating, concentration of 10 μM) was used for ‘non-specific’ controls(0% FAAH activity). 20 μl of 7.5 μM AAMCA substrate (in FAAH assaybuffer) was then added to all wells and incubated at room temperaturefor a further 1.5 hours. Fluorescence was determined at an excitationwavelength of 355 nm and an emission wavelength of 460 nm using aFlexstation plate reader (Molecular Devices, UK). Inhibition of FAAHactivity, by the compounds, was determined as the percentage reductionin relative fluorescence units (RFU) compared to the ‘total’ controls(in the absence of compound) minus the ‘non-specific’ controls. IC₅₀values were determined, from 10-point dose response curves, in XL-Fitusing a 4-Parameter Logistic Model (Sigmoidal Dose-Response Model).

The following Table 1 provides the 3-hour incubation results of testingthe compounds of Examples 1-4 herein in the above rat FAAH inhibitionassay.

TABLE 1 FAAH Rat IC50 (nM) Example No 180 minutes n 2 279 6 1 135 11 377 2 4 67 4

Part B Human FAAH 1 Assay

Human FAAH 1 activity was determined by measuring the liberation of thehighly fluorescent 7-amino, 4-methyl Coumarin (AMC) generated duringhydrolysis of the substrate arachidonoyl 7-amino, 4-methyl coumarinamide (AAMCA) by FAAH. Inhibition of human FAAH 1 activity wasdetermined as a percentage reduction of the fluorescence determined inthe absence of compound.

The assay was carried out in black-walled, clear bottom, 384-wellplates. 27.5 dl of human FAAH 1 protein (in FAAH assay buffer: 50 mMHepes, 0.01% Triton X-100, 1 mM EDTA, 0.5 mg/ml BSA (fatty-acid-free),pH 8.2) was pre-incubated, at 10 nM, with increasing concentrations ofcompounds (2.5 μl in 100% DMSO) for 1 hour at room temperature. 2.5 d ofDMSO was added for ‘total’ controls (100% FAAH activity) and 2.5 μl ofURB-597, a known inhibitor of FAAH activity, (at a final, saturating,concentration of 10 &M) was used for ‘non-specific’ controls (0% FAAHactivity). 20 d of 7.5 μM AAMCA substrate (in FAAH assay buffer) wasthen added to all wells and incubated at room temperature for a further4 hours. Fluorescence was determined at an excitation wavelength of 355nm and an emission wavelength of 460 nm using a Flexstation plate reader(Molecular Devices, UK). Inhibition of human FAAH 1 activity, by thecompounds, was determined as the percentage reduction in relativefluorescence units (RFU) compared to the ‘total’ controls (in theabsence of compound) minus the ‘non-specific’ controls. IC₅₀ values weredetermined, from 10-point dose response curves, in XL-Ft using a4-Parameter Logistic Model (Sigmoidal Dose-Response Model).

Table 2 shows the 1 hour incubation results of testing the compounds ofExamples 5 to 19 herein in the above human FAAH Inhibition assay.

TABLE 2 FAAH Human IC50 (nM) 60 minutes Example No (n = 2) 5 9 6 73 7 198 18 9 3 10 49 11 19 12 12 13 38 14 14 15 7 16 42 17 12 18 16 19 26

Rat Carrageenan Induced Thermal Hyperalgesia Model of Inflammatory Pain.

Male Wistar rats were assessed for thermal pain sensitivity by applyinga focused light beam onto the hind paws and recording the time to pawwithdrawal, before and after local intraplantar administration ofcarrageenan. After 3 h. thermal pain sensitivity was reassessed intreated and untreated hind paws prior to dosing with test compound orvehicle. Indomethacin was administered as a positive control.

Procedure

Male Sprague Dawley rats were tail-marked, and acclimatized to theplantar boxes on 3 separate occasions (6, 5 and 1 day prior to the testday) for at least 5 min on each occasion. On the pre-test day, the ratswere habituated to the test room for at least 30 min prior to testing.The rats were put into the Hargreaves plantar boxes, allowed to settledown for approx 3-5 min, and challenged with the mobile radiant heatsource. The latency to withdraw both left and right hindpaws from theheat source was determined on 2 occasions (3 min apart). The mean acrossthe 2 challenges was recorded as the baseline for each animal. Rats 18and 30 were not used in the study as they had very high baselinereadings, and they were replaced by 61 and 63. Rats were then allocatedto drug treatments ensuring the baseline latencies were balanced acrossgroups.

On the test day, rats received intraplantar carrageenan lambda (100 uLof 1% in saline), or saline in right hindpaw 3 hours before testing.Four hours before testing, rats received VER-158416 (1, 3, or 10 mg/kg)or vehicle (5% EtOH: 95% (1% methylcellulose in water) p.o.Subsequently, 30 min before testing, rats received a second injection ofeither indomethacin 10 mg/kg or vehicle (50% 0.1M Na₂CO₃: 47.5%phosphate buffered saline (PBS):2.5% 1M HCl) i.p. At the scheduled testtime following drug treatment, the latency to withdraw the paw from theradiant heat source was reassessed by a single reading.

For example, the compound of Example 13 above was tested as follows:Rats were dosed with intraplantar carrageenan at t=0; the compound ofExample 13 (1, 3 & 10 mg/kg po) or vehicle (5% EtOH: 95% (1%methylcellulose in water) at t=2 h; indomethacin (10 mg/kg ip) orvehicle at t=2.5 h and thermal sensitivity was measured at t=3 h. Thusall rats received both oral and ip dosing.

The compound of Example 13 (1, 3, 10 mg/kg p.o.) caused a dose-relatedinhibition of carrageenan-induced thermal hypersensitivity, whichreached statistical significance (cf. vehicle/carrageenan group; one wayANOVA followed by Newman-Keuls post hoc tests) at 3 and 10 mg/kg doses.The compound did not reduce pain sensitivity to below normal levels, andhad no effect on contralateral paw sensitivities to thermal pain. Themaximum effect of the compound was similar to that of the positivecontrol indomethacin.

REFERENCES

-   Hargreaves, K., Dubner, R., Brown, F., Flores, C., Joris, J.,    (1988). A new and sensitive method for measuring thermal nociception    in cutaneous hyperalgesla. Pain, 32, 77-48.-   Hedo, G., Laird, J. M. A., Lopez-Garcia, J. A., (1999). Time course    of spinal sensitization following carrageenan-induced inflammation    in the young rat: a comparative electrophysiological and behavioural    study in vitro and in vivo. Neuroscience, 92, 309-318-   Morris, C. J., (2003). Carrageenan-induced paw edema in the rat and    mouse. Methods in Mol Biol., 225, 115-121.

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof:

wherein Ar¹ is optionally substituted phenyl or optionally substitutedmonocyclic heteroaryl having 5 or 6 ring atoms; Ar² is optionallysubstituted phenyl, optionally substituted monocyclic heteroaryl having5 or 6 ring atoms or optionally substituted fused bicyclic heteroarylhaving 5 or 6 ring atoms in each fused ring; and Ar³ is a divalentradical selected from the group consisting of optionally substitutedphenylene and optionally substituted monocyclic heteroarylene radicalshaving 5 or 6 ring atoms.
 2. A compound as claimed in claim 1 whereinAr¹ is optionally substituted phenyl.
 3. A compound as claimed in claim1 wherein Ar² is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl,any of which being optionally substituted.
 4. A compound as claimed inclaim 1 wherein Ar² is 3-pyridyl, pyrimidin-4-yl, pyrazin-2-yl orpyridazin-3-yl, any of which being optionally substituted.
 5. A compoundas claimed in claim 1 wherein Ar³ is an optionally substituted divalentphenylene or pyridinylene radical.
 6. A compound as claimed in claim 5wherein Ar³ is an optionally substituted divalent 1,4-phenylene or a2,5-pyridinylene radical of formula:

wherein the bond marked with a single asterisk is attached to Ar¹ andthe bond marked with a double asterisk is attached to the oxygen.
 7. Acompound as claimed in claim 1 wherein any optional substituents in Ar¹,Ar² and Ar³ are independently selected from chloro, fluoro, bromo,cyclopropyl, methyl, mono-, di- or tri-methyl, trifluoromethyl,difluoromethyl, monofluoromethyl, methoxy, ethoxy, propoxy, butoxy,pentoxy, 2-methoxyethoxy, 2-benzyloxy-ethoxy, 2-hydroxy-ethoxy, mono-,di- or tri-fluoromethoxy, cyano, hydroxyl; —CO₂Ri and —SO₂Ri wherein R₁is hydrogen, methyl or ethyl; tetrazolyl; —NR₂R₃, —CH₂NR₂R₃ and—C(═O)NR₂R₃ wherein R₂ and R₃ are independently hydrogen, methyl orethyl.
 8. A compound as claimed in claim 1 wherein: Ar² is 3-pyridyl,pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl; Ar³ is an optionallysubstituted divalent 1,4-phenylene or a 2,5-pyridinylene radical offormula:

wherein the bond marked with a single asterisk is attached to Ar1 andthe bond marked with a double asterisk is attached to the oxygen; andAr¹ is optionally substituted phenyl.
 9. A compound as claimed in claim8 wherein Ar¹ is phenyl, 2-fluorophenyl, 3-(2-methoxy-ethoxy)-phenyl, or2-methoxy-5-(2-methoxy-ethoxy)-phenyl.
 10. A compound as claimed inclaim 8 wherein Ar² is pyridazin-3-yl
 11. A pharmaceutical compositioncomprising a compound as claimed in claim 1, together with one or morepharmaceutically acceptable carriers and/or excipients.
 12. A method oftreatment of a disease or medical condition which benefits frominhibition of FAAH activity, comprising administering to a subjectsuffering such disease or condition an effective amount of a compound asclaimed in claim
 1. 13. The method as claimed in claim 12 wherein thedisease or condition is selected from among acute or chronic pain,vertigo, vomiting, nausea, eating disorders, neurological andpsychiatric pathologies, acute or chronic neurodegenerative diseases,epilepsy, sleeping disorders, cardiovascular diseases, renal ischaemia,cancers, immune system disorders, allergic diseases, parasitic, virahorbacterial infectious diseases, inflammatory diseases, osteoporosis,ocular complaints, pulmonary complaints, gastrointestinal diseases,glaucoma related hypertension and urinary incontinence.
 14. The methodas claimed in claim 12 wherein the disease or condition is anxiety,depression, pain, inflammation, pruripus, a sleep disorder or a movementdisorder.